1. Field of the Invention
The present invention relates to use of a compound, particularly use of butylidenephthalide (Bdph), a method of using the same, and a method for preparing a pharmaceutical composition containing the same.
2. Description of the Related Art
Due to the increased survival time of modern people, more and more people face a variety of diseases affecting the health and also the problem of aging appearance with increased age and multiplied life stress. Specifically, Alzheimer's disease is the most prevalent neurodegenerative disease in the whole world, and the main pathological features comprise excessive deposition of β-amyloid protein (Aβ) forming the Aβ plaque in the brain (Glenner and Wong 1984; and Masters, C. L. et al., 1985) and intracellular neurofibrillary tangles (NFT) (Grundke-lqbal, I. et al., 1986; and Goedert, M. et al., 1988). The Aβ plaque is produced from amyloid protein precursor (APP) after cleavage by the β-site amyloid precursor protein cleaving enzyme (BACE) (Hussain, I. et al., 1999; and Vassar, R. et al., 1999) and the γ-secretase (Wolfe, M. S. et al., 1999; and Yu, G. et al., 2000), and consists essentially of Aβ40 and Aβ42 (Jarrett, J. T. et al., 1993). Large intra- and extracelluar accumulation of Aβ is a main cause of neuronal cell death.
The pathogenesis of Down's syndrome is uneven split of the 21th pair of chromosomes during meiosis, causing 1 additional chromosome to exist in the cell. The gene encoding the APP is located on the chromosome 21 (Rumble, B. et al., 1989; and Selkoe, D. J., 1996). It is generally accepted that the over-expression of APP leads to a symptom of early cognitive impairment in the patients with Down's syndrome (Burger, P. C. and F. S. Vogel, 1973). At present, many studies show that the Aβ plaque is found in the brain of patients with Down's syndrome (Masters, C. L. et al., 1985; Beyreuther, K. et al., 1992; Gyure, K. A. et al., 2001; and Mori, C. et al., 2002). Other studies show that the nerve cells produced by induced pluripotent stem cells (iPSCs) derived from patients with Down's syndrome can be used to reproduce the typical pathological features of Alzheimer's disease, for example, accumulation of Aβ42 and Aβ40, highly phosphorylated Tau protein, and others. Therefore, an iPSC differentiation system from patients with Down's syndrome can be used as a platform for screening drugs for treating or preventing Aβ-related neurodegenerative diseases.
The drugs for treating Alzheimer's disease currently available in clinic comprise cholinesterase inhibitors (Birks, J., 2006) and NMDA receptor antagonists (McShane, R. et al., 2006), both of which are suitable for improving the cognitive function of patients with Alzheimer's disease. However, the diseases derived from Alzheimer's disease, such as depression, insomnia, and so on, need to be treated with other suitable medications (Tariot, P. N. et al., 2004; Feldman, H. et al., 2006; and Howard, R. et al., 2012). Moreover, the two types of drugs can only ameliorate the symptoms, and cannot achieve the efficacy of curing Alzheimer's disease (Farlow, M. R. et al., 2010). Besides, in many studies, drugs for treating Alzheimer's disease are designed for reducing Aβ accumulation in the brain (Hong-Qi, Y. et al., 2012), and comprise specifically BACE inhibitors, for example, MK-8931 and ACI-91 (Mullard A., 2012), γ-secretase inhibitors, for example, LY450139 (Siemers, E. et al., 2005) and BMS-708163 (Tong, G. et al., 2012), or antibodies against Aβ by way of immunization.
Furthermore, although problems such as local alopecia, hair loss, or hypotrichosis do not adversely affect the health of an individual, they undeniably affect the appearance of the individual. Research suggests that those with hypotrichosis are prone to poor mood and unable to socialize, and may suffer from psychological problems such as social anxiety, insufficient self-confidence, and self-identity. Therefore, hypotrichosis or hair loss has become a problem received more and more attention at present.
In addition to the way to retarding the hair loss by changing the hair washing and dietary habits, there are many products for ameliorating the hair loss or promoting the hair growth available at present. The products are mainly divided into two classes, one class is vasodilators, and the other is prostaglandin-related derivatives. Further, among the vasodilators, the most well-known is “Regoine” (trade name minoxidil; Messenger A. G. et al., 2004), which is mainly composed of 2,4-diamino-6-piperidinopyrimidine 3-oxide. However, Regoine does not perform well for the hypotrichosis in each case, and the effect persists only when the product is used. Once the product is withdrawn, the newly grown hair will fall off again. It is reported that the prostaglandins F2α and E2 can be used to promote the eyelash and hair growth (Woodward, D. F. et al., 2013), but cause the side effects such as redness, irritation, pigmentation and the like to the user. Moreover, once the product is withdrawn, the newly grown hair will fall off too.
Butylidenephthalide (Bdph) is present in natural plants, for example, plants of the Apiaceae and Asteraceae family, and may be obtained by extraction with acetone and chloroform. Previous studies show that Bdph is useful in the treatment of spasm (Ko, W. C. et al., 1980) and inhibition of platelet aggregation (Teng, C. M. et al., 1987), and can suppress the cell growth and promote the cancer cell death. For example, the efficacy of inhibiting the tumor growth can be achieved by inhibiting the telomerase (Huang, M. H. et al., 2014; and Tsai, N. M. et al., 2006), and the efficacy of inhibiting the inflammatory response can be achieved by inhibiting NF-κB (Fu, R. H. et al., 2011). Furthermore, recent studies also show that Bdph can maintain the growth of embryonic stem cells and promote the formation of iPSCs by activating the Jak2/stat3 signaling pathway (Liu, S. P. et al., 2012).
The Wnt protein is a highly conserved secretary molecule, and an important factor for regulating the embryonic development and the stem cell maintenance. Wnt forms a ternary structure by binding to its receptor Frizzled (Frz) and LDL receptor-related proteins on the cell membrane, and acts on the Dishevelled (Dsh) in the cells.
Dsh binds to GSK-3β, the adenomatous polyposis coli protein and the Axin protein to inhibit the activity of GSK-3β, thereby inhibiting the β-catenin phosphorylation and the pathway of β-catenin degradation via ubiquitination. Activation of the Wnt signaling can induce the intracellular accumulation of β-catenin. After entering the nucleus, the β-catenin can activate other particular transcription factors, such as T-cell factors, lymphoid enhancer factors and Siamois, etc., to regulate the growth of cells and the development of an individual. Over or under activation of the Wnt signaling in the cells can cause damage to the organism, cause defects in early embryonic development, or cause tumor formation or dysfunction in late adulthood (Fodde, R. et al., 2007).
At present, many researches confirm that the efficacy of promoting the hair growth can be achieved with activation of Wnt by stimulating the replication of epidermal stem cells (Lim, X. et al., 2013). The epidermal stem cells are mostly present in hair follicle bulges, which are label-retaining cells, usually in a dormant state, and activated only when the epidermis is damaged or the tissue needs to be freshed. The Wnt/β-catenin pathway is an imoportant component in the maintenance of self-replication of epidermal stem cells. Activation of the Wnt signaling allows the dormant epidermal stem cells to enter a cell cycle for cell replication and differentiation into mature hair cells (Thompson, C. C. et al., 2006). Wnt7a expression can increase the number of hair follicles reproduced. Similarly, the β-catenin level in the nucleus can be increased by stabilizing the β-catenin against degradation via ubiquitination, thereby promoting the formation of new hair follicles (Gat, U. et al., 1998). On the contrary, inhibition of the Wnt signaling can prevent the formation of hair follicles caused by wounds (Ito, M. et al., 2007).
It can be known from the foregoing description that the prior art cannot provide an effective composition having no side effects for treating or preventing neurodegenerative diseases such as Alzheimer's disease; as well as for improving alopecia or promoting the hair growth. Therefore, it is the most important research topic at present to develop a novel composition effective in improvement or treatment of the above-mentioned symptoms.